Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2000-10-27
2002-07-16
Reamer, James H. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S539000, C514S541000
Reexamination Certificate
active
06420424
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the use of phenylalanine amide derivatives, and pharmaceutical compositions containing these compounds as Chemokine/CCR-3 receptor antagonists.
Chemokines are a superfamily of small secreted proteins. There are approximately 30 distinct chemokines known with many others being characterized. See Oppenheim et al., Properties of the Novel Proinflammatory Supergene “Intercrine” Cytokine Family,
Ann. Rev. Immun.,
9, 617-648 (1991); and Baggiolini, et al., Interleukin-8 and Related Chemotactic Cytokines-CXC and CC Chemokines,
Adv. Immun.,
55, 97-179 (1994). The properties of the chemokines suggest that they are essential for leukocyte trafficking and inflammatory processes, and are thus important components in a number of disease states. See Kita et al., Chemokines Active on Eosinophils: Potential Roles in Allergic Inflammation,
J. Exp. Med.,
183, 2421-2426 (1996); Strieter, et al., “The Good, the Bad and the Ugly” The Role of Chemokines in Models of Human Diseases,
J. Immun.,
157, 3583-3586 (1996); and Baggiolini, Eotaxin: a VIC (Very Important Chemokine) of Allergic Inflammation,
J. Clin. Invest.,
97,587 (1996).
Chemokines mediate their effects via interactions with 7TM-G-protein coupled receptors on the surface of immune and inflammatory cells. Eosinophils are proinflammatory granulocytes that play a major role in allergic diseases, such as bronchial asthma, allergic rhinitis, pruritis and atopic dermatitis. Upon activation, eosinophils release lipid mediators, cytotoxic proteins, oxygen metabolites and cytokines, all of which have the potential to produce pathophysiology. Numerous studies have demonstrated the presence of eosinophils or eosinophil-specific products in inflamed tissues in human diseases.
The mechanisms responsible for the selective infiltration of eosinophils in allergic diseases have yet to be clarified. Recently, a CC chemokine, eotaxin, was identified in guinea pigs and demonstrated to be present in a guinea pig model of allergic airway inflammation. See Jose, et al., Eotaxin: A Potent Eosinophil Chemoattractant Cytokine Detected in Guinea Pig Model of Allergic Airways Inflammation,
J. Exp. Med.,
179, 881-887 (1994); and Jose, et al., Eotaxin: Cloning of an Eosinophil Chemoattractant Cytokine and Increased mRNA Expression in Allergen-challenged Guinea-pig Lungs,
Biochem. Biophys. Res. Comm.,
205, 788-794 (1994). The human homologue of Guinea-pig eotaxin has been expressed and has been shown to induce eosinophil infiltration when injected into the skin of the rhesus monkey. See Ponath, et al., Cloning of the Human Eosinophil Chemoattractant, Eotaxin: Expression, Receptor Binding, and Functional Properties Suggest a Mechanism for Selective Recruitment of Eosinophils,
J. Clin. Invest.,
97, 604-612 (1996).
The cloning, expression and characterization of a novel C—C chemokine receptor, designated CCR-3 from peripheral blood eosinophils and from an eosinophil cDNA library have also been reported. See Kitaura, et al., Molecular Cloning of Human Eotaxin, an Eosinophil-selective CC Chemokine, and Identification of a Specific Eosinophil Eotaxin Receptor, CC Chemokine Receptor 3,
J. Biol. Chem.,
271, 7725-7730 (1996); Ahuja, et al., Cloning and Functional Expression of a Human Eosinophil CC Chemokine Receptor,
J. Biol. Chem.,
270, 16491-16494 (1995); Daugherty, et al., Cloning, Expression and Characterization of the Human Eosinophil Eotaxin Receptor,
J. Exp. Med.
183,,2349-2354 (1996); and Ponath, et al., Molecular Cloning and Characterization of a Human Eotaxin Receptor Expressed Selectively on Eosinophils,
J. Exp. Med.,
183, 2437-2448 (1996).
Eotaxin, MCP-4 and, to a lesser extent, RANTES and MCP-3 activate this receptor. The CCR-3 receptor is expressed at high levels on eosinophils; typically 40,000-400,000 receptors per cell are present. This is 10-100 fold more than the other chemokine receptor (CCR-1) expressed in eosinophils. Monoclonal antibodies raised to the CCR-3 receptor demonstrate that the receptor is primarily restricted to eosinophils and a subset of Th2 T-cells. This restricted expression on eosinophils and T-cells may be responsible for the selective recruitment of eosinophils and Th2 T-cells in allergic inflammation. Additionally, CCR-3 is potently activated by eotaxin 1, eotaxin and MCP-4. See Stellato et al., Production of the Novel CC Chemokine MCP-4 by Airway Cells and Comparison of Its Biological Activity to other CC-Chemokines.
J. Clin. Invest.
99, 92-936 (1997). In contrast, other known chemokines appear to activate more than one chemokine receptor, e.g. RANTES binds to CCR-1, CCR-3, CCR-4 and CCR-5 receptors.
The foregoing research advances have provided the impetus to investigate the inhibition of eosinophil-specific chemokines in order to examine its role in blocking cellular infiltration in inflamed tissues. CCR-3 receptor antagonists thus offer a unique approach toward decreasing the pathophysiology associated with allergic diseases. Antagonism of this receptor may be useful in the treatment of allergic disorders, including but not limited to bronchial asthma, allergic rhinitis, eczema, nasal polyposis, conjunctivitis, atopic dermatitis, inflammatory bowel disorder and pruritis.
SUMMARY OF THE INVENTION
The present invention involves phenylalanine amide derivatives represented by Formula (1) hereinbelow and their use as CCR-3 receptor antagonists which is useful in the treatment of a variety of diseases associated with allergic disorders, including but not limited to bronchial asthma, allergic rhinitis, nasal polyposis, atopic dermatitis and pruritis.
The present invention further provides methods for antagonizing CCR-3 receptors in an animal, including humans, which comprises administering to a subject in need of treatment an effective amount of a compound of Formula (I) or (II) as indicated hereinbelow.
DETAILED DESCRIPTION OF THE INVENTION
The compounds useful in the present methods are selected from Formula (I) or (II) hereinbelow:
wherein
n is an integer from 0 to 3;
R
1
is selected from the group consisting of N-carbobenzoxy-L-Phe, N-Ac-L-Pro, C
1-6
alkyl, OC
1-4
alkyl, aryl and heteroaryl, unsubstituted, monosubstituted, disubstituted or trisubstituted, with any substituents being independently selected from the group consisting of C
1-4
alkyl, COaryl, OCH
2
O, NO
2
, Cl and OCH
3
.
R
2
represents C
1-4
alkyl or benzyl;
m is an integer from 1 to 3: and
R
3
is independently selected from the group consisting of OH, OC
1-4
alkyl, NO
2
, NH
2
, halo, naphthyl, and OCOphenyl; or
wherein R represents indolylmethyl, phenyl or (CH
2
)
2
phenyl.
Preferably, in Formula(I), n represents 1
Preferably, in Formula(I), at the R
1
position, alkyl represents cC
6
H
11
or n-Bu. Preferably, O-alkyl represents O-t-Bu. Preferably, aryl represents phenyl or naphthyl. Preferably, heteroaryl represents thienyl, furyl, pyridyl, or quinolinyl.
Preferably, substituents at R
1
are independently selected from the group consisting of C
1-2
alkyl, CO-phenyl, OCH
2
O, NO
2
, Cl, OH, and OCH
3
.
Preferably, at R
2
, alkyl moieties are methyl or ethyl.
A preferred halo moiety at R
3
is iodo.
Preferably, in Formula (II), the carbon atom marked with the asterix (*) represents an S configuration.
Preferred compounds of the present invention include:
(S)-Ethyl-2-(1-napthoylamino)3-(4-nitrophenyl)propionate,
(S)-Isopropyl-2-(1-napthoylamino)3-(4-nitrophenyl)propionate,
(S)-Methyl-2-(1-napthoylamino)3-(4-nitrophenyl)propionate,
(S)-Benzyl-2-(1-napthoylamino)3-(4-nitrophenyl)propionate,
(S)Ethyl-2-(1-napthoylamino)3-(4-chlorophenyl)propionate,
(S)-Ethyl-2-benzoylamino-3-(4-hydroxyphenyl)propionate,
(S,S)-Ethyl-2-(2-benzyloxycarbonylamino-3-phenylpropionylamino)-3-(4-hydroxyphenyl)propionate,
(S,S)-Ethyl-2-(N-acetylpyrrolidine-2-benzoylamino)-3-(4-hydroxy-phenyl)propionate,
(S)-Ethyl-2-cyclohexanylamino-3-(4-hydroxyphenyl)propionate,
(S)-Ethyl-2-(3,3-diphenylpropionylamino)-3-(4-hydroxyphenyl)propionate,
(S)-Ethyl-2-(3-phenylpropionylamino)-3-(4-hydroxyphenyl)propionate,
Dhanak Dashyant
White John R.
Widdowson Katherine L.
King William T.
Kinzig Charles M.
Reamer James H.
Simon Soma G.
SmithKline Beecham Corporation
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